The overall goal of the Baltimore Huntington's Disease Center is to conduct interdisciplinary studies of the clinical and basic science of HD in order clarify pathogenesis, facilitate the design and interpretation of clinical trials, and identify and characterize therapeutic targets. Project 1 will identify factors, including CAG repeat length, that influence clinical presentation and longitudinal progression, in order to clarify HD pathogenesis, and facilitate the design and interpretation of future clinical trials. Project 1 will also conduct clinical-pathologic studies. Project 2 will use MRI technology to chart the cross sectional and longitudinal course of brain changes at all stages of HD, including change in the striatum and cerebral cortical gray and white matter, as well as functional studies. Project 3 will focus on the earliest identifiable changes that may initiate pathogenic processes, especially post-translational modification of huntingtin. Proteolytic cleavage and phosphorylation of huntingtin will be studied in cell and mouse models, and in HD post mortem tissue. These projects will be supported by four cores. Core A will provide administration and overall scientific direction. Core B will provide longitudinal clinical and neuropsychological assessments of individuals with HD or at risk for HD, and infrastructure for imaging, genetic and other assessments for use in Projects 1 and 2 and Core D. Core C will provide postmortem examination and diagnosis, and tissue for Project 3, and support the quantitative clinical pathologic studies in Project 1. Core D will provide genetic diagnosis of HD and HD-related disorders, and accurate data on CAG expansion length for use by all projects.